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Prognostic value of patient-derived xenograft engraftment in pediatric sarcomas
Helena Castillo-Ecija1,2, Guillem Pascual-Pasto1,2, Sara Perez-Jaume1,2
1Institut de Recerca Sant Joan de Deu, Barcelona, Spain.
Insights
Patient-derived xenograft (PDX) engraftment in pediatric sarcoma models correlates with poorer patient outcomes. Successful PDX models from newly diagnosed patients indicate a higher risk of relapse or refractory disease, highlighting their prognostic value.
Area of Science:
- Oncology
- Translational Research
- Pediatric Cancer
Background:
- Patient-derived xenografts (PDX) are valuable tools for cancer research.
- Understanding factors influencing PDX engraftment and their prognostic implications is crucial for pediatric sarcomas.
Purpose of the Study:
- To identify factors associated with successful PDX engraftment in pediatric sarcomas (Ewing sarcoma, osteosarcoma, rhabdomyosarcoma).
- To investigate the correlation between PDX engraftment and patient prognosis.
Main Methods:
- Established 30 subcutaneous PDX models from pediatric sarcoma patient tumor biopsies using immunodeficient mice.
- Assessed engraftment rates and correlated them with patient factors (age, disease status, tumor type, biopsy site).
- Evaluated PDX model fidelity (histology, chromosomal aberrations) and response to irinotecan, comparing it to patient responses.
Main Results:
- Achieved a 44% PDX engraftment rate.
- Older age (>12 years) and relapsed disease were associated with higher engraftment rates.
- PDX models retained key biological characteristics and showed functional stability with irinotecan treatment.
- PDX engraftment from newly diagnosed patients was a significant predictor of poor prognosis (p=0.040).
- In standard-risk newly diagnosed Ewing sarcoma, PDX engraftment predicted higher relapse/refractory disease risk (p=0.0357).
Conclusions:
- PDX engraftment is a significant prognostic factor for worse outcomes in newly diagnosed pediatric sarcoma patients.
- PDX models are biologically stable and can replicate patient responses to therapy.
- These findings underscore the utility of PDX models in predicting treatment outcomes for pediatric sarcomas.
Abstract:
The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.
